Summary Many drugs are bitter and overcoming this bitter taste is a major barrier in developing a successful product for pediatric patients. Compliance rates as low as 11% have been reported in children due to palatability/taste as well as swallowability and dose flexibility issues, all of which are addressed in this proposed project. Our overall goal is to develop a micron-sized, taste masked drug delivery platform for a wide range of drugs that can be readily incorporated into a variety of oral dosage forms suitable for pediatric patients, including suspensions, orally dissolving tablets, other multiparticulate systems, and orodispersible films. Such a broadly applicable taste masking delivery platform could be used for any poorly palatable chemical entity, which could facilitate the drug development process, allowing more palatable products to reach pediatric patients more rapidly and at reduced costs. We propose a novel two-step spray drying process to prepare sealed microparticles. Spray drying is commonly used in the pharmaceutical industry to prepare microparticles for incorporation into various dosage forms. These particles, however, are matrices, where drug is distributed throughout the particle, including on the surface, which can thus interact with taste buds when administered orally. Therefore, conventional spray drying does not effectively mask taste, especially for aggressively bitter drugs. In the proposed project, we will prepare conventional matrix microparticles then apply a second coating using pharmaceutically acceptable polymers that are insoluble in the saliva but readily soluble in the stomach. This second coating will sequester drug on the exterior surface of the matrix microparticles and prevent interaction with taste buds. Moreover, the pH-dependent solubility of these polymers will allow the spray drying process to be completely aqueous-based and thus we avoid the use of organic solvents and the toxicological and environmental issues associated with their use. We hypothesize that sealed matrix microparticles will be more palatable than conventional spray dried matrices. After characterizing the microparticles for size, morphologic structure and in vitro dissolution in both simulated saliva and gastric fluid, we will test our hypothesis using a randomized, double blind clinical study with an age-stratified pediatric taste panel. Children will rate palatability of the formulations using a seven point facial hedonic scale. The two model bitter drugs selected for the proposed project are acetaminophen (water-soluble) and ibuprofen (poorly water-soluble). These are well-known bitter drugs that are routinely and safely used in pediatric patients and represent a range of aqueous solubilities to assess the applicability of this novel two-step spray drying technique as a taste masking platform for both soluble and poorly soluble drugs.